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Title: Gain-of-function Lipoprotein Lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site

Author
item RICHARDSON, KRIS
item NETTLETON, JENNIFER - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item ROTLAN, NOEMI - NEW YORK UNIVERSITY SCHOOL OF MEDICINE
item TANAKA, TOSHIKO - NATIONAL INSTITUTE ON AGING (NIA, NIH)
item SMITH, CAREN - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY
item Lai, Chao Qiang
item Parnell, Laurence
item LEE, YU-CHI - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY
item LAHTI, JARI - UNIVERSITY OF HELSINKI
item LEMAITRE, ROZENN - UNIVERSITY OF WASHINGTON MEDICAL SCHOOL
item MANICHAIKUL, ANI - UNIVERSITY OF VIRGINIA SCHOOL OF MEDICINE
item KELLER, MARGAUX - TEMPLE UNIVERSITY MEDICAL SCHOOL
item MIKKILA, VERA - UNIVERSITY OF HELSINKI
item NGWA, JULIUS - BOSTON UNIVERSITY MEDICAL CENTER
item VAN ROOIJ, FRANK J. A. - ERASMUS MEDICAL CENTER
item BALLENTYNE, CHRISTIE - BAYLOR COLLEGE OF MEDICINE
item BORECKI, INGRID - WASHINGTON UNIVERSITY SCHOOL OF MEDICINE
item CUPPLES, L. ADRIENNE - FRAMINGHAM HEART STUDY
item GARCIA, MELISSA - NATIONAL INSTITUTES OF HEALTH (NIH)
item HOFMAN, ALBERT - ERASMUS MEDICAL CENTER
item FERRUCCI, LUIGI - NATIONAL INSTITUTE ON AGING (NIA, NIH)
item MOZAFFARIAN, DARIUS - BRIGHAM & WOMEN'S HOSPITAL
item PERALA, MIA-MARIA - HELSINKI HOSPITAL
item RAITAKARI, OLLI - UNIVERSITY OF TURKU
item TRACY, RUSSELL - UNIVERSITY OF VERMONT
item ARNETT, DONNA - UNIVERSITY OF ALABAMA
item BANDINELLI, STEFANIA - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item BOERWINKLE, ERIC - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item ERIKSSON, JOHAN - UNIVERSITY OF HELSINKI
item FRANCO, OSCAR - ERASMUS MEDICAL CENTER
item KAHONEN, MIKA - TAMPERE UNIVERSITY HOSPITAL
item NALLS, MICHAEL - NATIONAL INSTITUTE ON AGING (NIA, NIH)
item SISCOVICK, DAVID - UNIVERSITY OF WASHINGTON MEDICAL SCHOOL
item HOUSTON, DENISE - WAKE FOREST SCHOOL OF MEDICINE
item PSATY, BRUCE - UNIVERSITY OF WASHINGTON
item VIIKARI, JORMA - UNIVERSITY OF TURKU
item WITTEMAN, JACQUELINE C. M - ERASMUS MEDICAL CENTER
item GOODARZI, MARK - CEDARS-SINAI MEDICAL CENTER
item LEHTIMAKI, TERHO - UNIVERSITY OF TAMPERE MEDICAL SCHOOL
item LIU, YONGMEI - WAKE FOREST SCHOOL OF MEDICINE
item ZILLIKENS, M. CAROL - HARVARD SCHOOL OF PUBLIC HEALTH
item CHEN, YII-DER - CEDARS-SINAI MEDICAL CENTER
item UITTERLINDEN, ANDRE - HARVARD SCHOOL OF PUBLIC HEALTH
item ROTTER, JEROME - CEDARS-SINAI MEDICAL CENTER
item FERNANDEZ-HERNANDO, CARLOS - NEW YORK UNIVERSITY SCHOOL OF MEDICINE
item ORDOVAS, JOSE - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY

Submitted to: The American Journal of Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/26/2012
Publication Date: 1/10/2013
Citation: Richardson, K., Nettleton, J.A., Rotlan, N., Tanaka, T., Smith, C.E., Lai, C., Parnell, L.D., Lee, Y., Lahti, J., Lemaitre, R.N., Manichaikul, A., Keller, M., Mikkila, V., Ngwa, J., Van Rooij, F., Ballentyne, C.M., Borecki, I.B., Cupples, L., Garcia, M., Hofman, A., Ferrucci, L., Mozaffarian, D., Perala, M., Raitakari, O., Tracy, R.P., Arnett, D.K., Bandinelli, S., Boerwinkle, E., Eriksson, J.G., Franco, O.H., Kahonen, M., Nalls, M., Siscovick, D.S., Houston, D.K., Psaty, B.M., Viikari, J., Witteman, J., Goodarzi, M.O., Lehtimaki, T., Liu, Y., Zillikens, M., Chen, Y.I., Uitterlinden, A.G., Rotter, J.I., Fernandez-Hernando, C., Ordovas, J. 2013. Gain-of-function Lipoprotein Lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site. The American Journal of Human Genetics. 92(1):5-14.

Interpretive Summary: The human genome project has allowed for unprecedented access to human genetic data, and using these data, Genome Wide Association Studies (GWAS) have identified hundreds of common human genetic variants correlated with a significant change in lipid concentrations. However, there have been few hypotheses put forth, and fewer tested, to explain the biological mechanism through which the genetic variant may be modulating lipid concentrations. Here we combine computational biology, epidemiological, and molecular biology techniques to provide both association and functional evidence for the common variant rs13702 in Lipoprotein Lipase (LPL), an enzyme crucial for the processes of fat metabolism, modulating both human triacylglycerols (TAG) and high-density lipoprotein cholesterol (HDL-C) concentrations. We also demonstrate that greater intake of dietary polyunsaturated fatty acids (PUFA) can further enhance the favorable effect of this variant on TAG levels. Our association data replicate previous findings and our functional data provide biological relevance for rs13702. This information may be relevant to pharmacological and/or dietary regimens targeting lower TAG concentrations.

Technical Abstract: Genome wide association studies (GWAS) have identified hundreds of genetic variants that are associated with lipid phenotypes. However, data supporting a functional role for these variants in the context of lipid metabolism are scarce. We investigated the association of the Lipoprotein Lipase (LPL) variant rs13702 with plasma lipids and explored its potential for functionality. The rs13702 minor allele had been predicted to disrupt a microRNA (miR) recognition element (MRE) seed site (MRESS) for the human microRNA-410 (miR-410). Furthermore, rs13702 is in linkage disequilibrium (LD) with several SNPs identified by GWAS. We performed a meta-analysis across 10 cohorts of participants which showed a statistically significant association of rs13702 with triacylglycerols (TAG) (P = 3.18x10-42) and v(P = 1.35x10-32) with each copy of the minor allele associated with 0.060 mmol/L lower TAG and 0.041 mmol/L higher HDL-C. Our data showed that an LPL 3’ UTR luciferase reporter carrying the rs13702 major T allele was reduced by 40% in response to a miR-410 mimic. We also evaluated the interaction between intake of dietary fatty acids and rs13702. Meta-analysis demonstrated a significant interaction between rs13702 and dietary polyunsaturated fatty acid (PUFA) with respect to TAG concentrations (P= 0.00153), with the magnitude of the inverse association between dietary PUFA intake and TAG concentration showing -0.007 mmol/L greater reduction. Our results suggest rs13702 induces the allele-specific regulation of LPL by miR-410 in humans. This work provides biological and potential clinical relevance for previously reported GWAS variants associated with plasma lipid phenotypes.